Substituted 5-(pyrazin-2-yl)-1 h-pyrazolo[3,4-b]pyridine and pyrazolo[3,4-b]pyridine derivatives as protein kinase inhibitors are described in US Patent Publication No. 2013/0102586 and International Publication No. WO2012/135631.
Salt Inducible Kinase 2 (SIK2) (SEQ ID NO: 11) is a centrosome kinase required for bipolar mitotic spindle formation and is a Ser/Thr kinase. Three isoforms of SIK family have been reported; SIK1 (SNF1LK) (SEQ ID NO: 10), SIK2 (SNF1LK, QIK) (SEQ ID NO: 11) and SIK3 (QSK) (SEQ ID NO: 24). The SIK2 (SEQ ID NO: 11) is amplified in large B-cell lymphoma, ovarian, melanoma and beast cancer patients. Recent findings suggest that SIK2 (SEQ ID NO: 11) over expression enhanced cell death after ischemia and metabolic diseases as well. Inhibition of SIK2 (SEQ ID NO: 11) was reported to cause SIK2-dependent centrosome splitting in interphase while SIK2 (SEQ ID NO: 11) depletion blocked centrosome separation in mitosis, sensitizing ovarian cancers to paclitaxel in culture and in xenografts. Depletion of SIK2 (SEQ ID NO: 11) also delayed G1/S transition and reduced AKT phosphorylation. Higher expression of SIK2 (SEQ ID NO: 11) significantly correlated with poor survival in patients with high-grade serous ovarian cancers (Bast, Jr., et al., Cancer Cell., 18, 109-121, 2010) and is a plausible therapeutic target for therapy in ovarian cancers.
The Salt Inducible Kinase 2 (SIK2) (SEQ ID NO: 11) depletion in cancer cells had a significant decrease in cancer cell growth, delayed mitotic progression and G1/S transition and decreased AKT phosphorylation. Deficiency of SIK2 (SEQ ID NO: 11) significantly sensitized cancer cells to taxnae and paclitaxel in vivo xenograft models in interfering with mitotic progression. In this work we established the basis of utilizing SIK2 (SEQ ID NO: 11) as a target for therapy in cancer by evaluating its effect on taxane, paclitaxel sensitization in a panel of cell lines, confirming activity in xenografts that the SIK2 (SEQ ID NO: 11) is over-expressed in 30% of ovarian cancers and to further develop an assay to measure SIK2 (SEQ ID NO: 11) activity. Ovarian Cancer (OC) accounts 3% of cancers in women and is the fifth leading cause of cancer related death among women. Nearly 22,240 women were diagnosed in 2013 with OC in US alone with about 14,030 women estimated to die from this deadly gynecologic malignancy of American women. Ovarian cancer is one of the cancers difficult to detect prior to its advanced stage. The currently available treatments, other than surgery and radiation, are chemotherapeutics and the few approved targeted agents.
Additionally, an advantage of SIK2 (SEQ ID NO: 11) inhibitors that block SIK2 (SEQ ID NO: 11) activity is to recruit melanogenesis. This leads to recovery of brown hair in 6 to 8 weeks.
Recent reports suggests that the over expression of SIK2 (SEQ ID NO: 11) controlled the TORC1 (Transducer of regulated CREB activity-1) from entering the nucleus and activating CREB, and this enhanced cell death after ischemia. The SIK2 (SEQ ID NO: 11) inhibitor could enhance CREB (cAMP Responsive Element-Binding) protein activity and prevent neuron death in response to ischemia. The SIK2 (SEQ ID NO: 11) deficient mice were protected from stroke suggests that SIK2 degradation after ischemia is required for neurons.
There continues to be a need for new drugs to treat multiple cancer indications, melanogenesis, stroke, cardiovascular, obesity and type II diabetes diseases where SIK2 (SEQ ID NO: 11) and its isoforms play a pivotal role in these multiple disease indications. Using the homology structure of the SIK2 (SEQ ID NO: 11) and our FFDD (Fragment Field Drug Design) or FIELDS guided lead identification, screening and SAR efforts; we have discovered the first-in-class novel H-pyrrolo[2,3-b]pyridine and 1H-pyrazolo[3,4-b]pyridine inhibitors of SIK2 (SEQ ID NO: 11) that would be useful for treating multiple disease indications, including cancer (ovarian, breast, prostate, diffuse large B-cell lymphoma and melanoma), stroke, obesity, type II diabetes. We disclose here the composition and method of use for inhibitors of SIK2 (SEQ ID NO: 11).
Accordingly, the present invention is directed to composition and method of use for novel H-pyrrolo[2,3-b]pyridine and 1H-pyrazolo[3,4-b]pyridine inhibitors of SIK2 (SEQ ID NO: 11) and SIK3 (SEQ ID NO: 24) useful for treating multiple disease indications, including cancer (ovarian, breast, prostate, diffuse large B-cell lymphoma, lung, NSCL and melanoma), autophagy function, stroke, obesity, and type II diabetes.